Supplementary Figure S1. Analysis of the integrated cohort of breast tumors A - Correlation of proteomic data of all the tumor samples in the integrated cohort of 145 samples. Pearson correlation coefficients between the tumor samples ranged from 0.35 to 0.85. The color code in the vertical dendrogram represent the datasets and the one in the horizontal dendrogram represent the tumor subtypes. B-D - mRNA expression of IDH1, ACLY and IDH2 in the tumors of the Pan Cancer Atlas study (TCGA). Expression levels in breast invasive carcinoma is highlighted. E - mRNA expression (TCGA) of the subunits of IDH3 enzyme (IDH3A, IDH3B and IDH3G) in four breast cancer subtypes. IDH3 subunits showed inconsistent expression patterns between the subtypes.
ARTICLE ABSTRACT
Cancer-specific metabolic phenotypes and their vulnerabilities represent a viable area of cancer research. In this study, we explored the association of breast cancer subtypes with different metabolic phenotypes and identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple-negative breast cancer (TNBC) and HER2. Functional assays combined with mass spectrometry–based analyses revealed the oncogenic role of IDH2 in cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration, and antioxidant defense. Genome-scale metabolic modeling identified phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase (PSAT1) as the synthetic dosage lethal (SDL) partners of IDH2. In agreement, CRISPR-Cas9 knockout of PHGDH and PSAT1 showed the essentiality of serine biosynthesis proteins in IDH2-high cells. The clinical significance of the SDL interaction was supported by patients with IDH2-high/PHGDH-low tumors, who exhibited longer survival than patients with IDH2-high/PHGDH-high tumors. Furthermore, PHGDH inhibitors were effective in treating IDH2-high cells in vitro and in vivo. Altogether, our study creates a new link between two known cancer regulators and emphasizes PHGDH as a promising target for TNBC with IDH2 overexpression.
These findings highlight the metabolic dependence of IDH2 on the serine biosynthesis pathway, adding an important layer to the connection between TCA cycle and glycolysis, which can be translated into novel targeted therapies.
